Features of biliary tract diseases in ketamine abusers: a systematic review of case reports

Background and aims Anesthesiologists prefer ketamine for certain surgeries due to its effectiveness as a non-competitive inhibitor of the N-methyl-D-aspartate receptor in the brain. Recently, this agent has also shown promise as an antidepressant. However, ketamine can cause hallucinogenic effects and is sometimes abused as an illicit drug. Ketamine abuse has been associated with liver and bile duct complications. This systematic study aims to better understand cholangiopathy in ketamine abusers by reviewing case reports. Methods and material In this systematic review, a comprehensive literature search was conducted with the terms “biliary tract diseases” and “ketamine”. Case reports and case series of adult patients with documented ketamine abuse and reported cholangiopathy or biliary tract disease were included. We extracted the data of relevant information and the results were reported through narrative synthesis and descriptive statistics. Results A total of 48 studies were initially identified, and 11 studies were finally included in the review. The mean age of the patients was 25.88 years. Of the 17 patients, 64.7% were men. Symptoms often included abdominal pain, nausea, and vomiting. Most patients were discharged with improved symptoms and liver function. Common bile duct dilation and other findings were observed in imaging results and other diagnostic studies. Conclusion This review highlights the diverse presentations and diagnostic modalities used in ketamine-induced cholangiography. These patients tend to be young men with deranged liver function tests and abdominal pain, which should be taken into consideration. These patients often require a multidisciplinary approach in their management.


Introduction
Ketamine is a synthetic phencyclidine derivative with both analgesic and anesthetic properties [1].It has a molecular weight of 237.72 g/mol and its pKa is about 7.5 [2].Its onset of action is within 30 seconds of intravenous administration and it has a half-life of 2.5 hours [3].Ketamine is metabolized by liver through N-demethylation and hydroxylation, which is in turn excreted into urine (90%) and bile (10%) [4].This substance acts as an antagonist on N-methyl-D-aspartate (NMDA) receptors and noncompetitively blocks glutamate [5].
Anesthesiologists favor ketamine over other agents for certain surgical procedures, and this medication has been widely used for this purpose since its discovery in 1962 [6].It has also been used as an antidepressant in recent years and has shown promising results [7].However, ketamine can also exert hallucinogenic effects, vivid imagery, and short-term excitement, and is used as an illicit drug via oral or inhalation routes [8].Ketamine medical use has been associated with hepatobiliary complications, which is well established in the literature [9,10].Burned patients who receive large accumulative doses of ketamine are more prone to develop these complication [11,12].Recently, critically ill patients with coronavirus disease 2019 (COVID- 19) have also been afflicted with biliary tract diseases such as secondary sclerosing cholangitis [13].Moreover, similar to burned patients, ketamine abusers who consume large quantities of the drug are susceptible to biliary tract disease [14].
Despite its rarity, there are multiple case reports that address cholangiopathy in ketamine abusers.However, to the best of our knowledge, there is no methodological study that presents the findings of these case reports to give us a better understanding of this complication.Thus, the present systematic review of case reports is designed to better characterize the features of cholangiopathy in ketamine abusers.

Literature search and eligibility criteria
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline to conduct the present systematic review.We carried out a thorough literature search in PubMed, Google Scholar, and Web of Science using the Medical Subject Headings (MeSH) terms "biliary tract diseases" and "ketamine" from inception until October 2023.The full search terms are outlined in the appendix.We did not limit the preliminary search results with any filters.Furthermore, to avoid missing any pertinent article, we hand-searched the references of each selected study.The diagram explaining the selection process is depicted in Fig. 1.Studies were included if they met the following inclusion criteria: (1) were case reports or case series of adult patients aged 18 years or older, (2) patients with documented ketamine abuse, (3) patients with reported cholangiopathy or biliary tract disease, and (4) were written in English

Selection of studies
The studies retrieved by the initial search were examined independently by two reviewers (AT and HN).As the first step, we identified the duplicates and removed them.The search results were then truncated to case reports (could be published as letter, correspondence, commentary, and so on) with at least one patient developing cholangiopathy following ketamine administration.Afterward, each paper was evaluated for eligibility on the basis of title, abstract, and full text.If a full-text article was unavailable, the correspondent was contacted for a copy, and in case of disagreement between the reviewers, a decision was made by consensus or by consulting a third reviewer (AN).The selected studies contained information about diagnosis, laboratory tests and imaging, demographics (for example, age and sex), liver function tests, and the outcomes of the disease.

Data extraction and quality assessment
We extracted the following items after the final selection: study region and year, demographics of patients, past medical history, presenting signs and symptoms, liver function test results, ketamine abuse pattern and duration, imaging findings (for example, ultrasound and magnetic resonance imaging), biopsy and cytology findings, treatment approach, and outcome of the disease (that is,.deceased or discharged).To minimize the effect of biases, we assessed the quality of each included study with a standardized tool [15].A narrative synthesis was used to report the results and descriptive statistics were used to calculate the frequency and percentage for categorical variables, as well as mean and standard deviation for continuous variables.

Study characteristics and patients' clinical information
Overall, 48 studies (PubMed = 19, Web of Science = 29) were identified through our initial search, of which 4 were duplicates and removed.A total of 33 studies were excluded on the basis of title and abstract, and finally 11 studies were included in this review [16][17][18][19][20][21][22][23][24][25][26].The study selection process is outlined in Fig. 1.Studies were conducted from 2009 through 2020 in the UK [5], China [2], Hong Kong [3], and the USA [1].Mean age was 25.88 ± 4.95 years, ranging from 18 to 38 years.Of the 17 patients, 11 (64.7%) were men and 6 were women.We found that three patients were concurrent alcohol abusers and two patients were human immunodeficiency virus (HIV) positive.Urinary tract infection (UTI) was observed in three patients, and two patients had a history of acute renal failure (ARF).A total of 15 patients presented with epigastric or right upper quadrant abdominal pain, along with other signs and symptoms such as nausea, vomiting, and fever.As for the other two patients, one of them was referred because of deranged liver function tests and the other had urinary symptoms.Jaundice and hepatomegaly were detected in one patient.Liver function tests (LFTs) were not reported for one patient and two patients had normal LFT.The initial alanine aminotransferase (ALT) levels were available for 11 patients, with a calculated mean of 232.09 ± 148.14 IU/L, ranging from 75 to 521 IU/L.These patients had been abusing ketamine for 3 months to 15 years (median 2 years).Of 17 patients, 9 received endoscopic retrograde cholangiopancreatography (ERCP) for treatment, and other treatment approaches included drug rehabilitation program, catheterization, biliary drainage, and conservative therapy.Except for one patient who lacked outcome information, all patients were discharged with improved symptoms and LFT results.

Imaging results and other diagnostic studies
The main imaging modalities that were used across the studies were ultrasound (US), magnetic resonance cholangiopancreatography (MRCP), computed tomography (CT), and hepatobiliary iminodiacetic acid (HIDA) scan, which were utilized in 13, 9, 10, and 3 patients, respectively.In addition, the findings of ERCP, which is mainly a therapeutic approach, were reported in five patients.Common bile duct (CBD) dilation was visualized in 12 patients.The investigators detected strictures in three patients and gallstone in one patient.HIDA scan showed diminished gall bladder ejection fraction in one patient and was normal in the other two patients.Other diagnostic studies, including brush cytology, colonoscopy, and biopsies, were performed in a subgroup of nine patients.These findings are all summarized in Table 1.

Discussion
This study provides valuable information about the characteristics of patients who presented with ketamineinduced cholangiopathy.The mean age of the patients was 25.88 ± 4.95 years, with a range from 18 to 38 years.Men accounted for 64.7% of the patients, while women accounting for the remaining 35.3%.Additionally, three patients were found to be alcohol abusers and two were HIV positive.Among the patients, three had UTIs and two had a history of ARF.The epidemiology of other biliary diseases, such as primary sclerosing cholangitis with a 2:1 male to female ratio, is comparable to our results [27].The patients involved in this review were rather young, which can be explained by the recreational nature of the ketamine abuse.Concomitant alcohol abuse is quite common in ketamine abuser population and can be up to 25% [28].Due to the possible cytotoxic effect of ketamine on urothelium, patients often experience urinary symptoms [29].This explains the resurgence of urinary symptoms in the patients included in this review.The most common presenting symptom was epigastric or right upper quadrant abdominal pain, which was reported by 15 patients and also witnessed in clinical practice.Two other patients either presented with deranged liver function tests or urinary symptoms.LFTs were available for all but one patient, with two patients having normal LFT results.The initial ALT was measured in 11 patients, with a mean value of 232.09 ± 148.14 IU/L, ranging from 75 to 521 IU/L.The upper limit of normal value (ULN) for ALT is 30 IU/L in men and 19 IU/L in women [30].The reported ALT levels in this review are more than twice the ULN and should be considered pathologic and require more workup [31].It is suggested that ketamine hepatotoxicity can result in LFT derangements similar to that of drug-induced liver injury [32].This effect can be augmented via inhibiting CYP32A enzyme, which is a hepatic enzyme responsible for ketamine breakdown [33], and is also demonstrated by an animal study [34].
The duration of ketamine abuse ranged from 3 months to 15 years, with a median of 2 years.The therapeutic dose for ketamine varies depending on its indication.Anesthesia, pain management, and depression require a dose of 1 mg/kg, 0.4 mg/kg, and 0.5 mg/kg, respectively [35][36][37].The consumed ketamine dose in this review is patient-reported and was up to 3 g per day, which is substantially higher than the accumulated therapeutic dose at first glance, which is held responsible for causing hepatobiliary disturbances in this population.In the current review, all patients except one, who lacked outcome information, were discharged with improved symptoms and LFT results.This is in contrast with the disease outcome in ketamine-induced cholangiopathy in critically ill patients, which had a significant mortality rate [38].This can be explained by the fact that the patients in this review did not have any underlying liver pathology and they were not in critical condition.
Imaging studies played a crucial role in the diagnosis and assessment of patients.The preferred method to visualize biliary tree was MRCP [39].Specifically, in the current review, 13 patients underwent ultrasound, 9 underwent MRCP, 10 underwent CT, and 3 underwent HIDA scans.In our study, HIDA revealed diminished gall bladder ejection fraction in one patient indicative of functional gallbladder dysfunction [40], while two patients had normal results.The most common imaging finding was common bile duct (CBD) dilation, observed in 12 patients.Similar to the results of this review, a retrospective study showed that CBD dilation in ketamineinduced cholangiopathy can be found in up to 69% of patients [41].
The growing bulk of evidence regarding the etiology of these complications is not consistent.At a molecular level, ketamine can potentially contribute to biliary tract dilation by affecting NMDA receptors on smooth muscle cells [42].Additionally, increased glutamate and NMDA concentration in dorsal motor nucleus of vagus nerve seem to increase gallbladder motility, which can be potentially antagonized by ketamine [20].This may, in turn, lead to strictures in biliary tract, chronic inflammation, and fibrosis [21].These conjectures of direct toxicity of ketamine are supported by several studies that were carried out to evaluate ketamine's effect on urinary system [43,44].An animal study by Thune et al. suggests that ketamine stimulates opiate receptors and is associated with an increase in flow resistance through the sphincter of Oddi [45].On the contrary, the results of sphincter of Oddi manometry in human subjects receiving low-dose ketamine for endoscopy does not support this claim [46].
This retrospective review was subject to several limitations.Due to the anecdotal nature of case reports, we could not draw robust conclusions.We used narrative synthesis for the most part and could not perform a meta-analysis due to the obvious heterogeneity.In addition, the number of patients who were selected was considerably low and several of them lacked relevant clinical data or were of low quality.We did not include retrospective observational studies that did not contain the details on individual patients.In spite of these limitations, this review used a systematic approach and endeavored to summarize the characteristics of biliary tract diseases in ketamine abusers.

Conclusion
The current review provides important clinical information regarding the characteristics of patients with ketamine-induced cholangiopathy.These patients tend to be young men with deranged LFT and abdominal pain.Our study also highlights the diverse presentations and diagnostic modalities used in assessing these patients, emphasizing the importance of a multidisciplinary approach in their management.

Table 1
Summary of study characteristics and patients' demographic, clinical, and imaging information